Lo Chia-Yun, Strobl Susan L, Dunham Kimberly, Wang Wei, Stewart Lucy, Misplon Julia A, Garcia Mayra, Gao Jin, Ozawa Tatsuhiko, Price Graeme E, Navidad Jose, Gradus Steve, Bhattacharyya Sanjib, Viboud Cecile, Eichelberger Maryna C, Weiss Carol D, Gorski Jack, Epstein Suzanne L
Gene Transfer and Immunogenicity Branch, Division of Cellular and Gene Therapies, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland.
Laboratory of Cell-Mediated Immunity, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland.
Open Forum Infect Dis. 2017 Feb 12;4(2):ofx023. doi: 10.1093/ofid/ofx023. eCollection 2017 Spring.
Antibody and T-cell immunity to conserved influenza virus antigens can protect animals against infection with diverse influenza strains. Although immunity against conserved antigens occurs in humans, whether such responses provide cross-protection in humans and could be harnessed as the basis for universal influenza vaccines is controversial. The 2009 pandemic provided an opportunity to investigate whether pre-existing cross-reactive immunity affected susceptibility to infection.
In 2009, we banked sera and peripheral blood mononuclear cells (PBMC) from blood donors, then monitored them for pandemic influenza infection (pH1N1) by polymerase chain reaction or seroconversion. Antibodies to hemagglutinin (HA), neuraminidase (NA), nucleoprotein (NP), matrix 2 (M2), and HA-pseudotypes were measured in sera. T-cell inteferon-γ enzyme-linked immunospot responses were measured in PBMC.
There were 13 infections in 117 evaluable donors. Pre-existing T-cell reactivity to pH1N1 was substantial (of 153 donors tested, 146 had >100 spot-forming cells/10 cells). Antibodies reactive with pH1N1 were common: anti-NP (all donors) and anti-M2 (44% of donors). Pseudotype-neutralizing antibodies to H1 were detected, but not to highly conserved HA epitopes. Unexpectedly, donors with symptomatic pH1N1 infection had sharp rises in HA pseudotype-neutralizing antibodies, not only pH1N1 but also against multiple seasonal H1s. In addition, an exploratory study of a T-cell marker (response to NP) identified probable infection missed by standard criteria.
Although the number of infections was inadequate for conclusions about mechanisms of protection, this study documents the wide variety of pre-existing, cross-reactive, humoral and cellular immune responses to pandemic influenza virus antigens in humans. These responses can be compared with results of other studies and explored in universal influenza vaccine studies.
针对保守的流感病毒抗原的抗体和T细胞免疫可保护动物免受多种流感毒株的感染。虽然人类中也存在针对保守抗原的免疫反应，但这种反应是否能在人类中提供交叉保护并可作为通用流感疫苗的基础仍存在争议。2009年的大流行提供了一个机会来研究预先存在的交叉反应性免疫是否会影响感染易感性。
2009年，我们收集了献血者的血清和外周血单核细胞（PBMC），然后通过聚合酶链反应或血清转化监测他们是否感染大流行性流感（pH1N1）。检测血清中针对血凝素（HA）、神经氨酸酶（NA）、核蛋白（NP）、基质2（M2）和HA假型的抗体。在PBMC中检测T细胞干扰素-γ酶联免疫斑点反应。
117名可评估的献血者中有13人感染。预先存在的对pH1N1的T细胞反应性很强（在153名接受检测的献血者中，146人的斑点形成细胞数/10⁶细胞>100）。与pH1N1反应的抗体很常见：抗NP（所有献血者）和抗M2（44%的献血者）。检测到针对H1的假型中和抗体，但未检测到针对高度保守的HA表位的抗体。出乎意料的是，有症状的pH1N1感染献血者中，HA假型中和抗体急剧上升，不仅针对pH1N1，还针对多种季节性H1。此外，一项对T细胞标志物（对NP的反应）的探索性研究发现了一些标准标准遗漏的可能感染情况。
虽然感染数量不足以得出关于保护机制的结论，但本研究记录了人类中针对大流行性流感病毒抗原预先存在的、交叉反应性的体液和细胞免疫反应的多样性。这些反应可与其他研究结果进行比较，并在通用流感疫苗研究中进行探索。
